This proposal deals with the relationship among the pharmacokinetics, stereo-specific cerebral binding to receptor sites,and pharmacodynamic effects of opiate drugs. Potential modulation of opiate in vivo receptor binding and effects by endogenous opioid peptides is also under investigation. Specific hypotheses to be tested include existence of multiple opiate receptor sites with various functions (e.g., mediating analgesia or addiction/withdrawal), participation of endogenous opioid peptides in maintaining the dependent state, and the action of opiate antagonists either through displacing agonists from their receptors or by binding to distinct antagonist specific receptor sites.